Mitochondrial encephalomyopathies are important causes of mental retardation. The investigators are focusing on disorders associated with mitochondrial DNA (mtDNA) point mutations, especially mitochondrial encephalomyopathy, lactic acidosis, and stroke-like episodes (MELAS). In Project I, Dr. Petra Kaufmann will continue to characterize the natural history of MELAS, correlating clinical course in probands and oligosymptomatic relatives with cerebral and muscle biomarkers assessed by MRSI and 31P-NMR. She will also initiate a clinical trial with idebenone, an effective ROS scavenger already tested in other mitochondrial disorders. This is a placebo controlled, randomized, blinded three-year study of a large cohort of MELAS patients. In Project II, Dr Eric Schon will concentrate on pharmacological approaches to mtDNA-related disorders by evaluating the effectiveness of compounds designed to facilitate electron transport through the respiratory chain in cybrid cultures grown under the pressure of ketogenic medium replacing glucose. He will also assess whether heteroplasmic shifting in ketogenic media is due to selective autophagy of mitochondria harboring mtDNA mutations. In Project III, Dr Mercy Davidson will employ an in vitro model of the blood-brain barrier (BBB) that she has constructed to confirm neuropathological data suggesting a breakdown of BBB function in MELAS. She will also test candidate therapeutic agents on the BBB model in which the co-cultures of human astrocytes and endothelial celis will be either normal or homoplasmic for the m.3243A>G MELAS mutation. In the Administrative Core, Dr Salvatore DiMauro and Dr. Michio Hirano will provide direction, administration, and external consultation. In the Technical Core, Dr. Ali Naini will provide technical service (tissue culture, cybrid generation), diagnostic tools (histochemistry, biochemistry, molecular genetics), and manage shared equipment for the project as a whole. RELEVANCE: Mitochondrial encephalomyopathies due to mutations in mtDNA are generally devastating diseases for which there is no effective therapy. The relevance of this program project is two-fold: (i) it will explore rational therapeutic approaches both in a clinical trial and in experimental settings;and (ii) it will directly or indirectly explore pathogenic mechanisms, which, in turn, may lead to novel therapeutic strategies.